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The global pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), named coronavirus disease 2019, has infected more than 8.9 million people worldwide. This calls for urgent effective therapeutic measures. RNAdependent RNA polymerase (RdRp) activity in viral transcription and replication has been recognized as an attractive target to design novel antiviral strategies. Although SARS-CoV-2 shares less genetic similarity with SARS-CoV (~79%) and Middle East respiratory syndrome coronavirus (~50%), the respective RdRps of the three coronaviruses are highly conserved, suggesting that RdRp is a good broad-spectrum antiviral target for coronaviruses. In this review, we discuss the antiviral potential of RdRp inhibitors (mainly nucleoside analogs) with an aim to provide a comprehensive account of drug discovery on SARS-CoV-2.
The hemagglutinin (HA) and neuraminidase (NA) of influenza A virus possess antagonistic activities on interaction with sialic acid (SA), which is the receptor for virus attachment. HA binds SA through its receptor-binding sites, while NA is a receptor-destroying enzyme by removing SAs. The function of HA during virus entry has been extensively investigated, however, examination of NA has long been focused to its role in the exit of progeny virus from infected cells, and the role of NA in the entry process is still under-appreciated. This review summarizes the current understanding of the roles of HA and NA in relation to each other during virus entry.
Lignans are widely produced by various plant species; they are a class of natural products that share structural similarity. They usually contain a core scaffold that is formed by two or more phenylpropanoid units. Lignans possess diverse pharmacological properties, including their antiviral activities that have been reported in recent years. This review discusses the distribution of lignans in nature according to their structural classification, and it provides a comprehensive summary of their antiviral activities. Among them, two types of antiviral lignans-podophyllotoxin and bicyclol, which are used to treat venereal warts and chronic hepatitis B (CHB) in clinical, serve as examples of using lignans for antivirals-are discussed in some detail. Prospects of lignans in antiviral drug discovery are also discussed.
Vaccination is the most prevalent prophylactic means for controlling seasonal influenza infections. However, an effective vaccine usually takes at least 6 months to develop for the circulating strains. Therefore, new therapeutic options are needed for the acute treatment of influenza infections to control this virus and prevent epidemics/pandemics from developing. We have discovered fast-acting, orally bioavailable acylated 4-aminopiperidines with an effective mechanism of action targeting viral hemagglutinin (HA). Our data show that these compounds are potent entry inhibitors of influenza A viruses. We present docking studies that suggest an HA binding site for these inhibitors on H5N1. Compound 16 displayed a significant decrease of viral titer when evaluated in the infectious assays with influenza virus H1N1 (A/Puerto Rico/8/1934) or H5N1 (A/Vietnam/1203/2004) strains and the oseltamivir-resistant strain with the most common H274Y mutation. In addition, compound 16 showed significant synergistic activity with oseltamivir in vitro.
Background
In the urgent campaign to develop therapeutics against SARS-CoV-2, natural products have been an important source of new lead compounds.
Results
We herein identified two natural products, ginkgolic acid and anacardic acid, as inhibitors using a high-throughput screen targeting the SARS-CoV-2 papain-like protease (PLpro). Moreover, our study demonstrated that the two hit compounds are dual inhibitors targeting the SARS-CoV-2 3-chymotrypsin-like protease (3CLpro) in addition to PLpro. A mechanism of action study using enzyme kinetics further characterized the two compounds as irreversible inhibitors against both 3CLpro and PLpro. Significantly, both identified compounds inhibit SARS-CoV-2 replication in vitro at nontoxic concentrations.
Conclusions
Our finding provides two novel natural products as promising SARS-CoV-2 antivirals.
Licorice
(Glycyrrhiza uralensis) is a popular
medicinal plant containing more than 70 flavonoid and triterpenoid
glycosides. Thus far, only a few reports are available on the glycosylation
enzymes involved in their biosynthesis. In this work, we mined the
transcriptome data of G. uralensis and discovered
43 candidate genes for O-glycosyltransferase (O-GT). Among them, 17 genes could be expressed in E. coli, and functions of the enzymes were analyzed by catalyzing
eight native substrates. As a result, we characterized 11 O-GTs, including isoflavone 7-O-GTs, flavonol
3-O-GTs, and promiscuous O-GTs catalyzing
flavones, chalcones, and triterpenoids. They could efficiently synthesize
key licorice compounds such as liquiritin, isoliquiritin, ononin,
and 3-O-β-d-glucuronosyl glycyrrhetinic
acid. The diversity of O-GTs contributes to the biosynthesis
of various glycosides in licorice. These enzymes could also be used
as biocatalytic tools to synthesize other bioactive O-glycosides.
The influenza A virus (IAV) causes seasonal epidemics and occasional but devastating pandemics, which are of a major public health concern. Although several antiviral drugs are currently available, there is an urgent need to develop novel antiviral therapies with different mechanisms of action due to emergence of drug resistance. In this study, two related compounds, chebulagic acid (CHLA) and chebulinic acid (CHLI), were identified as novel inhibitors against IAV replication. A reporter virus-based infection assay demonstrated that CHLA and CHLI exhibit no inhibitory effect on IAV entry or RNA replication during the virus replication cycle. Results of viral release inhibition assay and neuraminidase (NA) inhibition assay indicated that CHLA and CHLI exert their inhibitory effect on the NA-mediated viral release. Moreover, oseltamivir-resistance mutation NA/H274Y of NA is susceptible to CHLA or CHLI, suggesting a different mechanism of action for CHLA and CHLI. In summary, CHLA and CHLI are promising new NA inhibitors that may be further developed as novel antivirals against IAVs.
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